PROJECT SUMMARY Basic/Translational Investigations on Buprenorphine Treatment with buprenorphine is a therapeutic option for patients with substance abuse disorders. Buprenorphine is normally administered sublingually and the dose of buprenorphine is titrated to a response in individual subjects. Pregnant women appear to require a higher dose of buprenorphine compared to non- pregnant women. Our proposed basic/translational studies will complement the clinical study proposed and provide mechanistic information and data that cannot be normally obtained in pregnant women. We will study the effect of pregnancy on how buprenorphine in handled in pregnant using pregnant rats and isolated livers from pregnant rats. We will also study how buprenorphine alters various endogenous chemicals in the brain and hence the response to buprenorphine. Since patients are on chronic therapy with buprenorphine and placenta tends to accumulate a lot of buprenorphine, we will also evaluate the impact of buprenorphine on various enzymes and proteins in the placenta of pregnant women on buprenorphine in comparison to those not on buprenorphine. We will also study the ability of the fetal liver to metabolize any buprenorphine that crosses the placenta. We also plan to use computer simulations to predict what will happen to exposure of buprenorphine in the mother and fetus at various time points during pregnancy. Collectively our studies will help optimize dosing of buprenorphine in pregnant women and minimize non-adherence to this important treatment option.